Characterisation and modelling of the thermorheological properties of pharmaceutical polymers and their blends using capillary rheometry: Implications for hot melt processing of dosage forms.

Given the growing interest in thermal processing methods, this study describes the use of an advanced rheological technique, capillary rheometry, to accurately determine the thermorheological properties of two pharmaceutical polymers, Eudragit E100 (E100) and hydroxypropylcellulose JF (HPC) and their blends, both in the presence and absence of a model therapeutic agent (quinine, as the base and hydrochloride salt). Furthermore, the glass transition temperatures (Tg) of the cooled extrudates produced using capillary rheometry were characterised using Dynamic Mechanical Thermal Analysis (DMTA) thereby enabling correlations to be drawn between the information derived from capillary rheometry and the glass transition properties of the extrudates. The shear viscosities of E100 and HPC (and their blends) decreased as functions of increasing temperature and shear rates, with the shear viscosity of E100 being significantly greater than that of HPC at all temperatures and shear rates. All platforms were readily processed at shear rates relevant to extrusion (approximately 200–300 s−1) and injection moulding (approximately 900 s−1). Quinine base was observed to lower the shear viscosities of E100 and E100/HPC blends during processing and the Tg of extrudates, indicative of plasticisation at processing temperatures and when cooled (i.e. in the solid state). Quinine hydrochloride (20% w/w) increased the shear viscosities of E100 and HPC and their blends during processing and did not affect the Tg of the parent polymer. However, the shear viscosities of these systems were not prohibitive to processing at shear rates relevant to extrusion and injection moulding. As the ratio of E100:HPC increased within the polymer blends the effects of quinine base on the lowering of both shear viscosity and Tg of the polymer blends increased, reflecting the greater solubility of quinine within E100. In conclusion, this study has highlighted the importance of capillary rheometry in identifying processing conditions, polymer miscibility and plasticisation phenomena.

Leukaemogenesis, gene interplay, and the role of the haemopoietic environment

Malignant initiation, leukaemic transformation, and disease progression in haematological malignancies involves a series of mutational events in genes involved in normal housekeeping functions of the cell. These acquired genetic changes can lead to either increased proliferation or a decreased rate of apoptosis, thus allowing expansion of the malignant clone. Although leukaemia can arise as a de novo disease, it has become increasingly clear that therapies, including the use of irradiation and/or chemotherapy, can give rise to malignancy. Therapy-associated myelodysplasia (t-MDS) and therapy-associated acute myeloid leukaemia (t-AML) account for 10-20% of new cases of these diseases. Although these secondary malignancies have been recognised as a clinical entity for nearly 30 years, molecular studies are now pinpointing various regions of the genome that are susceptible to DNA damage by these chemotherapeutic/radiotherapeutic strategies. The detection of new malignancies (both solid tumours and haematological tumours) following allogeneic bone marrow transplantation (BMT) is also providing us with some clues to the nature of leukaemogenesis, particularly with the observation that leukaemia can occur in donor cells postallogeneic BMT.

Tullis Rennie's Muscle Memory: Listening to the Act of Listening

This paper explores a recent, broadly 'electroacoustic', fixed medium composition by Tullis Rennie, which uses his background in ethnographic fieldwork to explore (in this case through auto-ethnography) modes of listening, and the role of technologies in mediating this listening. Muscle Memory: A conversation about jazz, with Graham South (trumpet) (2014) begins to answer questions about how one work can comment on and analyse or critique another through its own agency as music, bringing composition and ethnography together in fruitful collision, and illuminating the human capacity to manipulate and be manipulated by musical activity. The paper uses the piece to test the extent to which four functions, identified by Simon Frith (1987. Towards an aesthetic of popular music. In R. Leppert & S. McClary (Eds.), Music and society (pp. 133-49). Cambridge: Cambridge University Press) as crucial to the meaningfulness of popular music may, in the context of ubiquitously technologised music, have broader application than he originally intended.

Dublin 1916: theatre of revolt

In his essay, Anti-Object, Kengo Kuma proposes that architecture cannot and should not be understood as object alone but instead always as series of networks and connections, relationships within space and through form. Some of these relationships are tangible, others are invisible. Stan Allen and James Corner have also called for an architecture that is more performative and operative – ‘less concerned with what buildings look like and more concerned with what they do’ – as means of effecting a more intimate and promiscuous relationship between infrastructure, urbanism and buildings. According to Allen this expanding filed offers a reclamation of some of the areas ceded by architecture following disciplinary specialization:

‘Territory, communication and speed are properly infrastructural problems and architecture as a discipline has developed specific technical means to deal with these variables. Mapping, projection, calculation, notation and visualization are among architecture’s traditional tools for operating at the very large scale’.

The motorway may not look like it – partly because we are no longer accustomed to think about it as such – but it is a site for and of architecture, a territory where architecture can be critical and active. If the limits of the discipline have narrowed, then one of the functions of a school of architecture must be an attempt occupy those areas of the built environment where architecture is no longer, or has yet to reach. If this is a project about reclamation of a landscape, it is also a challenge to some of the boundaries that surround architecture and often confine it, as Kuma suggests, to the appreciation of isolated objects.

M:NI 2014-15
We tend to think of the motorway as a thing or an object, something that has a singular function. Historically this is how it has been seen, with engineers designing bridges and embankments and suchlike with zeal … These objects like the M3 Urban Motorway, Belfast’s own Westway, are beautiful of course, but they have caused considerable damage to the city they were inflicted upon.

Actually, it’s the fact that we have seen the motorway as a solid object that has caused this problem. The motorway actually is a fluid and dynamic thing, and it should be seen as such: in fact it’s not an organ at all but actually tissue – something that connects rather than is. Once we start to see the motorway as tissue, it opens up new propositions about what the motorway is, is used for and does. This new dynamic and connective view unlocks the stasis of the motorway as edifice, and allows adaptation to happen: adaptation to old contexts that were ignored by the planners, and adaptation to new contexts that have arisen because of or in spite of our best efforts.

Motorways as tissue are more than just infrastructures: they are landscapes. These landscapes can be seen as surfaces on which flows take place, not only of cars, buses and lorries, but also of the globalized goods carried and the lifestyles and mobilities enabled. Here the infinite speed of urban change of thought transcends the declared speed limit [70 mph] of the motorway, in that a consignment of bananas can cause soil erosion in Equador, or the delivery of a new iphone can unlock connections and ideas the world over.

So what is this new landscape to be like? It may be a parallax-shifting, cognitive looking glass; a drone scape of energy transformation; a collective farm, or maybe part of a hospital. But what’s for sure, is that it is never fixed nor static: it pulses like a heartbeat through that most bland of landscapes, the countryside. It transmits forces like a Caribbean hurricane creating surf on an Atlantic Storm Beach: alien forces that mutate and re-form these places screaming into new, unclear and unintended futures.

And this future is clear: the future is urban. In this small rural country, motorways as tissue have made the whole of it: countryside, mountain, sea and town, into one singular, homogenous and hyper-connected, generic city.

Goodbye, place. Hello, surface!

Neutron Scattering of Aromatic and Aliphatic Liquids

Organic solvents, such as cyclohexane, cyclohexene, methylcyclohexane, benzene and toluene, are widely used as both reagents and solvents in industrial processes. Despite the ubiquity of these liquids, the local structures that govern the chemical properties have not been studied extensively. Herein, we report neutron diffraction measurements on liquid cyclohexane, cyclohexene, methylcyclohexane, benzene and toluene at 298 K to obtain a detailed description of the local structure in these compounds. The radial distribution functions of the centres of the molecules, as well as the partial distribution functions for the double bond for cyclohexene and methyl group for methylcyclohexane and toluene have been calculated. Additionally, probability density functions and angular radial distribution functions were extracted to provide a full description of the local structure within the chosen liquids. Structural motifs are discussed and compared for all liquids, referring specifically to the functional group and aromaticity present in the different liquids.

Design of an OFDM Physical Layer Encryption Scheme

This paper presents a new encryption scheme implemented at the physical layer of wireless networks employing orthogonal frequency-division multiplexing (OFDM). The new scheme obfuscates the subcarriers by randomly reserving several subcarriers for dummy data and resequences the training symbol by a new secure sequence. Subcarrier obfuscation renders the OFDM transmission more secure and random, while training symbol resequencing protects the entire physical layer packet, but does not affect the normal functions of synchronization and channel estimation of legitimate users while preventing eavesdroppers from performing these functions. The security analysis shows the system is robust to various attacks by analyzing the search space using an exhaustive key search. Our scheme is shown to have a better performance in terms of search space, key rate and complexity in comparison with other OFDM physical layer encryption schemes. The scheme offers options for users to customize the security level and key rate according to the hardware resource. Its low complexity nature also makes the scheme suitable for resource limited devices. Details of practical design considerations are highlighted by applying the approach to an IEEE 802.11 OFDM system case study.

Identification of protein complexes in Alzheimer's disease

A Doença de Alzheimer (AD) é a maior doença neurodegenerativa a nível mundial, e a principal causa de demência na população idosa. O processamento da proteína precursora de amilóide (APP) pelas β- e g- secretases origina o peptídeo Aβ, que agrega em oligómeros neurotóxicos e em placas senis. Estes são eventos-chave na patogénese da DA que levam à rutura da neurotransmissão sináptica, morte neuronal e inflamação neuronal do hipocampo e córtex cerebral, causando perda de memória disfunção cognitiva geral. Apesar dos grandes avanços no conhecimento do papel do processamento da APP na DA, a sua função fisiológica ainda não foi totalmente elucidada. Os mapas de interações proteína-proteína (PPI) humanos têm desempenhado um papel importante na investigação biomédica, em particular no estudo de vias de sinalização e de doenças humanas. O método dois-híbrido em levedura (YTH) consiste numa plataforma para a produção rápida de redes de PPI em larga-escala. Neste trabalho foram realizados vários rastreios YTH com o objetivo de identificar proteínas específicas de cérebro humano que interagissem com a APP, ou com o seu domínio intracelular (AICD), tanto o tipo selvagem como com os mutantes Y687F, que mimetizam o estado desfosforilado do resíduo Tyr-687. De facto, a endocitose da APP e a produção de Aβ estão dependentes do estado de fosforilação da Tyr-687. Os rastreios YTH permitiram assim obter de redes proteínas que interagem com a APP, utilizando como “isco” a APP, APPY687F e AICDY687F. Os clones positivos foram isolados e identificados através de sequenciação do cDNA. A maior parte dos clones identificados, 118, correspondia a sequências que codificam para proteínas conhecidas, resultando em 31 proteínas distintas. A análise de proteómica funcional das proteínas identificadas neste estudo e em dois projetos anteriores (AICDY687E, que mimetiza a fosforilação, e AICD tipo selvagem), permitiram avaliar a relevância da fosforilação da Tyr-687. Três clones provenientes do rastreio YTH com a APPY687F foram identificados como um novo transcrito da proteína Fe65, resultante de splicing alternativo, a Fe65E3a (GenBank Accession: EF103274), que codifica para a isoforma p60Fe65. A p60Fe65 está enriquecida no cérebro e os seus níveis aumentam durante a diferenciação neuronal de células PC12, evidenciando o potencial papel que poderá desempenhar na patologia da DA. A RanBP9 é uma proteína nuclear e citoplasmática envolvida em diversas vias de sinalização celulares. Neste trabalho caracterizou-se a nova interação entre a RanBP9 e o AICD, que pode ser regulada pela fosforilação da Tyr-687. Adicionalmente, foi identificada uma nova interação entre a RanBP9 e a acetiltransferase de histonas Tip60. Demonstrou-se ainda que a RanBP9 tem um efeito de regulação inibitório na transcrição mediada por AICD, através da interação com a Tip60, afastando o AICD dos locais de transcrição ativos. O estudo do interactoma da APP/AICD, modelado pela fosforilação da Tyr-687, revela que a APP poderá estar envolvida em novas vias celulares, contribuindo não só para o conhecimento do papel fisiológico da APP, como também auxilia a revelar as vias que levam à agregação de Aβ e neurodegeneração. A potencial relevância deste trabalho relaciona-se com a descoberta de algumas interações proteicas/vias de sinalização que podem que podem ser relevantes para o desenvolvimento de novas estratégias terapêuticas na DA.

Synthesis and functionalization of hydroxyapatite nanoparticles

Graças aos desenvolvimentos na área da síntese de nanomaterais e às potentes técnicas de caracterização à nanoescala conseguimos hoje visualizar uma nanopartícula (NP) como um dispositivo de elevado potencial terapêutico. A melhoria da sua efectividade terapêutica requer no entanto o aprofundamento e sistematização de conhecimentos, ainda muito incipientes, sobre toxicidade, selectividade, efeitos colaterais e sua dependência das próprias características físico-químicas da NP em análise. O presente trabalho, elegendo como alvo de estudo uma substância considerada biocompatível e não tóxica, a hidroxiapatite (Hap), pretende dar um contributo para esta área do conhecimento. Definiram-se como metas orientadoras deste trabalho (i) estudar a síntese de nanoparticulas de Hap (Hap NP), e a modificação das características físico-químicas e morfológicas das mesmas através da manipulação das condições de síntese; (ii) estudar a funcionalização das Hap NP com nanoestruturas de ouro e com ácido fólico, para lhes conferir capacidades acrescidas de imagiologia e terapêuticas, particularmente interessantes em aplicações como o tratamento do cancro (iii) estudar a resposta celular a materiais nanométricos, com propriedades físico-químicas diversificadas. No que se refere à síntese de Hap NP, comparam-se dois métodos de síntese química distintos, a precipitação química a temperatura fisiológica (WCS) e a síntese hidrotérmica (HS), em meios aditivados com ião citrato. A síntese WCS originou partículas de tamanho nanométrico, com uma morfologia de agulha, pouco cristalinas e elevada área superficial especifica. A síntese HS à temperatura de 180ºC permitiu obter partículas de dimensões também nanométricas mas com área específica inferior, com morfologia de bastonete prismático com secção recta hexagonal e elevada cristalinidade. Com o objectivo de aprofundar o papel de algumas variáveis experimentais na definição das características finais das partículas de hidroxiapatite, designadamente o papel do ião citrato (Cit), variou-se a razão molar [Cit/Ca] da solução reagente e o tempo de síntese. Demonstrou-se que o ião citrato e outras espécies químicas resultantes da sua decomposição nas condições térmicas (180ºC) de síntese tem um papel preponderante na velocidade de nucleação e de crescimento dessas mesmas partículas e por conseguinte nas características físico-químicas das mesmas. Elevadas razões [Cit/Ca] originam partículas de dimensão micrométrica cuja morfologia é discutida no contexto do crescimento com agregação. Com o objectivo de avaliar a citotoxicidade in vitro das nanopartículas sintetizadas procedeu-se à esterilização das mesmas. O método de esterilização escolhido foi a autoclavagem a 121º C. Avaliou-se o impacto do processo de esterilização nas características das partículas, verificando-se contrariamente às partículas WCS, que as partículas HS não sofrem alterações significativas de morfologia, o que se coaduna com as condições de síntese das mesmas, que são mais severas do que as de esterilização. As partículas WCS sofrem processos de dissolução e recristalização que se reflectem em alterações significativas de morfologia. Este estudo demonstrou que a etapa de esterilização de nanopartículas para aplicações biomédicas, por autoclavagem, pode alterar substancialmente as propriedades das mesmas, sendo pois criticamente importante caracterizar os materiais após esterilização. Os estudos citotoxicológicos para dois tipos de partículas esterilizadas (HSster e WCSster) revelaram que ambas apresentam baixa toxicidade e possuem potencial para a modelação do comportamento de células osteoblásticas. Tendo em vista a funcionalização da superfície das Hap NP para multifunções de diagnóstico e terapia exploraram-se condições experimentais que viabilizassem o acoplamento de nanopartículas de ouro à superfície das nanopartículas de Hidroxiapatite (Hap-AuNP). Tirando partido da presença de grupos carboxílicos adsorvidos na superfície das nanopartículas de Hap foi possível precipitar partículas nanométricas de ouro (1,5 a 2,5 nm) na superfície das mesmas adaptando o método descrito por Turkevich. No presente trabalho as nanopartículas de Hap funcionaram assim como um template redutor do ouro iónico de solução, propiciando localmente, na superfície das próprias nanopartículas de Hap, a sua redução a ouro metálico. A nucleação do ouro é assim contextualizada pelo papel redutor das espécies químicas adsorvidas, designadamente os grupos carboxílicos derivados de grupos citratos que presidiram à síntese das próprias nanopartículas de Hap. Estudou-se também a funcionalização das Hap NP com ácido fólico (FA), uma molécula biologicamente interessante por ser de fácil reconhecimento pelos receptores existentes em células cancerígenas. Os resultados confirmaram a ligação do ácido fólico à superfície das diferentes partículas produzidas HS e Hap-AuNPs. Graças às propriedades ópticas do ouro nanométrico (efeito plasmão) avaliadas por espectroscopia vis-UV e às potencialidades de hipertermia local por conversão fototérmica, as nanoestruturas Hap-AuNPs produzidas apresentam-se com elevado interesse enquanto nanodispositivos capazes de integrar funções de quimio e terapia térmica do cancro e imagiologia. O estudo da resposta celular aos diversos materiais sintetizados no presente trabalho foi alvo de análise na tentativa de se caracterizar a toxicidade dos mesmos bem como avaliar o seu desempenho em aplicações terapêuticas. Demonstrou-se que as Hap NP não afectam a proliferação das células para concentrações até 500 g/ml, observando-se um aumento na expressão genética da BMP-2 e da fosfatase alcalina. Verificou-se também que as Hap NP são susceptíveis de internalização por células osteoblásticas MG63, apresentando uma velocidade de dissolução intracelular relativamente reduzida. A resposta celular às Hap-AuNP confirmou a não citotoxicidade destas partículas e revelou que a presença do ouro na superfície das Hap NP aumenta a taxa proliferação celular, bem como a expressão de parâmetros osteogénicos. No seu conjunto os resultados sugerem que os vários tipos de partículas sintetizadas no presente estudo apresentam também comportamentos interessantes para aplicações em engenharia de tecido ósseo.

Characterisation of ZG16p, a unique mammalian lectin from pancreatic zymogen granules

The mechanisms of secretory granule biogenesis and regulated secretion of digestive enzymes in pancreatic acinar cells are still not well understood. To shed light on these processes, which are of biological and clinical importance (e.g., pancreatitis), a better molecular understanding of the components of the granule membrane, their functions and interactions is required. The application of proteomics has largely contributed to the identification of novel zymogen granule (ZG) proteins but was not yet accompanied by a better characterization of their functions. In this study we aimed at a) isolation and identification of novel membrane-associated ZG proteins; b) characterization of the biochemical properties and function of the secretory lectin ZG16p, a membrane-associated protein; c) exploring the potential of ZG16p as a new tool to label the endolysosomal compartment. First, we have performed a suborganellar proteomics approach by combining protein analysis by 2D-PAGE and identification by mass spectrometry, which has led to the identification of novel peripheral ZGM proteins with proteoglycan-binding properties (e.g., chymase, PpiB). Then, we have unveiled new molecular properties and (multiple) functions of the secretory lectin ZG16p. ZG16p is a unique mammalian lectin with glycan and proteoglycan binding properties. Here, I revealed for the first time that ZG16p is highly protease resistant by developing an enterokinase-digestion assay. In addition I revealed that ZG16p binds to a high molecular weight complex at the ZGM (which is also protease resistant) and forms highly stable dimers. In light of these findings I suggest that ZG16p is a key component of a predicted submembranous granule matrix attached to the luminal side of the ZGM that fulfils important functions during sorting and packaging of zymogens. ZG16p, may act as a linker between the matrix and aggregated zymogens due to dimer formation. Furthermore, ZG16p protease resistance might be of higher importance after secretion since it is known that ZG16p binds to pathogenic fungi in the gut. I have further investigated the role of ZG16p binding motifs in its targeting to ZG in AR42J cells, a pancreatic model system. Point mutations of the glycan and the proteoglycan binding motifs did not inhibit the targeting of ZG16p to ZG in AR42J cells. I have also demonstrated that when ZG16p is present in the cytoplasm it interacts with and modulates the endo-lysosomal compartment. Since it is known that impaired autophagy due to lysosomal malfunction is involved in the course of pancreatitis, a potential role of ZG16p in pancreatitis is discussed.

‘Running with the Fox and Hunting with the Hounds’: Social Work Tutors' Experiences of Managing Failing Social Work Students in Practice Learning Settings

The paper explores the issues raised by social work students failing in practice learning settings from the perspective of university tutors, by drawing on existing literature in this area from social work and nursing, as well as findings from a small‐scale empirical qualitative study. The qualitative study was influenced by practitioner‐researcher and practice‐near paradigms; and is based on interviews with twelve social work tutors in England. The findings reveal that tutors are able to articulate the important tasks and functions of their roles when issues of failing students in practice learning settings arise, although the process can be challenging. The challenges include: supporting practice educator and student, concerns about other tutors’ practices, the difficulties in promoting appropriate professional standards and values within higher education contexts and frustrations with practice educators and placements. Only a third of the respondents (four) however, articulated their gate keeping roles and responsibilities although this was not without its difficulties. Given the current reforms in social work education in England at this present time, with greater emphasis on threshold standards at entry level, and at key stages throughout the programme of study, the research is timely in terms of the critical consideration of the tutor role and challenges inherent in promoting appropriate standards.

Joint inversion of geophysical and hydrologic data during water infiltration

Tese de doutoramento, Ciências Geofísicas e da Geoinformação (Geofísica), Universidade de Lisboa, Faculdade de Ciências, 2014

Methods for the transfer function design of multiple narrow-band bandpass sigma-delta modulators

This paper presents the design analysis of novel tunable narrow-band bandpass sigma-delta modulators, which can achieve concurrent multiple noise-shaping for multi-tone input signals. Four different design methodologies based on the noise transfer functions of comb filters, slink filters, multi-notch filters and fractional delay comb filters are applied for the design of these multiple-band sigma-delta modulators. The latter approach utilises conventional comb filters in conjunction with FIR, or allpass IIR fractional delay filters, to deliver the desired nulls for the quantisation noise transfer function. Detailed simulation results show that FIR fractional delay comb filter-based sigma-delta modulators tune accurately to most centre frequencies, but suffer from degraded resolution at frequencies close to Nyquist. However, superior accuracies are obtained from their allpass IIR fractional delay counterpart at the expense of a slight shift in noise-shaping bands at very high frequencies. The merits and drawbacks of each technique for the various sigma-delta topologies are assessed in terms of in-band signal-to-noise ratios, accuracy of tunability and coefficient complexity for ease of implementation.

Deciphering the mechanisms underlying the loss of BDNF neuroprotection in an Alzheimer’s disease model

Tese de mestrado, Neurociências, Faculdade de Medicina, Universidade de Lisboa, 2016

A comparative study of complex multiple-band noise-shaping sigma-delta modulators for multi-tone input signals

This paper presents a comparative study of complex single-bit and multi-bit sigma-delta modulators that are capable of providing concurrent multiple-band noise-shaping for multi-tone narrow-band input signals. The concepts applied for the three design methodologies are based on the noise transfer functions of complex comb, complex slink and complex multi-notch filters.

The metamorphosis of authority: a case study of the Aga Khan Development Network and the Ismaili Imamate

This research is a study of modern developments of the institutions of the Nizārī Ismaili imamate during the time of the present Ismaili Imam, Shāh Karīm al-Ḥusaynī, Aga Khan IV, as the 49th hereditary living Imam of Shiʿi Nizārī Ismaili Muslims, particularly addressing the formation of the Aga Khan Development Network (AKDN) and the functions of the Community institutions. Using the case study of the Aga Khan Development Network and the Nizārī Ismaili imamate, this research demonstrates that the three ideal types of authority as proposed by Weber, namely the traditional, charismatic and legal-bureaucratic types, are not sufficient to explain the dynamics of authority among Muslims. This is partly due to Weber’s belief in the uniqueness of Western civilisation, which is a product of his thesis on Protestant Ethics and partly because his ideal typical system does not work in the case of the Muslim societies. The Ismaili imamate with its multifarious institutions in contemporary times is the most suitable counter-example by which to powerfully demonstrate that Weberian models of authority fail to explain this phenomenon and it would indeed appear as a paradoxical institution if viewed with Weberian theses. The Ismaili imamate in contemporary times represents a paradigm shift and a transmutation not only as regards the Weberian models but also when viewed from inside the tradition of Shiʿi Muslim history. This evolutionary leap forward, which has been crystallised over the course of the past half a century, in the Ismaili imamate suggests the development of a new form of authority which is unprecedented. There are clearly various elements in this form of authority which could be discerned as rooted in tradition and history; however the distinctive elements of this new form of authority give it a defining and exciting dimension. There are several qualities which are peculiar to the contemporary condition of the Ismaili imamate and its style of leadership which are distinctive. Most importantly, while some central features, like succession by way of designation (naṣṣ) has not changed, there is one overarching quality which can best capture all these elements and that is the transmutation of the Ismaili imamate from the person of the Imam into the office of imamate and thus we are now facing the institutionalisation of the imamate and the office being the embodiment of the authority of the Imam. I have described this new development as a metamorphosis of the authority because it gives an entirely new form and content to the previously familiar concept of authority in the Shiʿi Ismaili Muslim tradition.